The broad goal of this NCNPDDG project is to isolate and identify new marine natural products from macroorganisms and cultural microorganisms, as leads for cancer therapy. We seek structures that will be useful against solid tumors for which there are few effective anti cancer drugs. There overall specific aims are: (a) To demonstrate that primary screens employing targets such as oncogene products, tumor suppressor gene products, proteins involved in various signal transduction pathways, and proteins involved in apoptosis, will be effective in uncovering new classes of anticancer drug leads. (b) To show that the primary and secondary screens will identify extracts of marine macro and micro organisms as sources of anticancer drug lead substances. (c) To confirm that the marine natural products, or derivatives thereof, selected by primary screens will be active against solid tumors such as breast, colon, lung, ovarian and prostate. (d) To illustrate that marine natural product drug leads identified by the primary and secondary screens will not act by established cytotoxicity based mechanisms. (e) To prove that marine macro and micro organisms will provide anticancer drug leads structurally different from those obtained from terrestrial sources. These objectives will be achieved by the union of natural products chemistry and molecular-based assays. Innovative approaches are represented both in the strategies to obtain marine natural products and in the design of the screens which incorporate new understanding of tumor biology and the molecular basis of cancer. Primary screens will be employed to broadly examine extracts of marine organisms (both collected and cultured) from the following groups: (a) sponges, (b) tunicates, (c) algae, (d) corals, (e) wild cyanophytes, (f) cyanophytes in sponges, (g) various cultured microalga, (h) cultured actinomycetes from sponges, (i) anaerobic and aerobic bacteria, and (j) fungi. Active principles will be isolated and their structures established. Primary screen active compounds will be further studied for their potency, breadth of activity, and in vivo efficacy. A decision network has been assembled to guide the follow-up of the best leads in secondary assays. The NCNPDDG participants (as listed below) have a strong record of collaborative research with one another. They represent different institutions and distinct scientific disciplines: Cancer Biology & Pharmaceutical Chemistry (Bair), Bioorganic Chemistry (Crews), Organic Chemistry (Davidson), Pharmaceutical Chemistry (Gerwick), Bioorganic Chemistry (Schmitz).